Loss of the endoplasmic reticulum protein Tmem208 affects cell polarity, development, and viability

作者：Debdeep Dutta, Oguz Kanca, Rishi V. Shridharan, Paul C. Marcogliese, Benjamin Steger, Marie Morimoto, F. Graeme Frost, Ellen F. Macnamara, Undiagnosed Diseases Network, Michael F. Wangler, Shinya Yamamoto, Andreas Jenny, David R. Adams, May Christine V. Malicdan, Hugo J. Bellen, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hugo J. Bellen, Lindsay C. Burrage, Hsiao‐Tuan Chao, Gary Clark, William J. Craigen, Hongzheng Dai, Fariha Jamal, Lefkothea Karaviti, Shamika Ketkar, Brendan Lee, Richard A. Lewis, Ronit Marom, Paolo Moretti, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Monika Weisz Hubshman, Kim C. Worley, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward M. Behrens, Kosuke Izumi, Marni J. Falk, Kelly Hassey, Kathleen E. Sullivan, Anna Raper, Gonench Kilich, Zhe Zhang, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie‐Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.‐G. Tan, Nicole M. Walley, Pankaj B. Agrawal, H. Diercks Alan, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances A. High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Shilpa N. Kobren, Amelia L.M. Tan, Rachel Mahoney, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Éva Morava, Devin Oglesbee, Güney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Pete Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy C. Levitt, Xue Zhong Liu, Jacob L. McCauley, Ralph L. Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Züchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos R. Ferreira, Rena A. Godfreyv, Catherine Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva H. Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa A. Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih M. Zein, Muhammad Yousef, Margaret P Adam, Laura M. Amendola, Michael J. Bamshad, Anita E. Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter H. Byers, Sirisak Chanprasert, Michae Cunningham, Katrina M. Dipple, Daniel Doherty, Dawn Earl, Ian A. Glass, Katie Golden‐Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike‐Pyne, Gail P. Jarvik, Jeffrey G. Jarvik, Suman Jayadev, Christina Lam, Kenneth R. Maravilla, Heather C. Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah A. Nickerson, Wendy H. Raskind, Natalie Rosenwasser, C. RonScott, Angela Sun, Virginia P. Sybert, Stephanie E Wallace, Mark H. Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernández, Paul G. Fisher, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Beth A. Martin, Shruti Marwaha, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano‐Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martín G. Martín, Julián A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves‐Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo D. Botto, John C. Carey, Laura Pace, Nicola Longo, Gábor Marth, Paolo Moretti, Aaron R. Quinlan, Matt Velinder, Dave Viskochil, Pınar Bayrak‐Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, J. Phillip Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica‐Krezel · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2322582121 · 被引用次数：6 · 研究领域：Endoplasmic Reticulum Stress and Disease、Cellular transport and secretion、Autophagy in Disease and Therapy

Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog CG8320/Tmem208 by replacing the gene with the Kozak-GAL4 sequence. We show that Tmem208 is broadly expressed in flies and that its loss causes lethality, although a few short-lived flies eclose. These animals exhibit wing and eye developmental defects consistent with impaired cell polarity and display mild ER stress. Tmem208 physically interacts with Frizzled (Fz), a planar cell polarity (PCP) receptor, and is required to maintain proper levels of Fz. Moreover, we identified a child with compound heterozygous variants in TMEM208 who presents with developmental delay, skeletal abnormalities, multiple hair whorls, cardiac, and neurological issues, symptoms that are associated with PCP defects in mice and humans. Additionally, fibroblasts of the proband display mild ER stress. Expression of the reference human TMEM208 in flies fully rescues the loss of Tmem208 , and the two proband-specific variants fail to rescue, suggesting that they are loss-of-function alleles. In summary, our study uncovers a rol...